Change in genome structure can occur in mitotic and meiotic cell lineages, and this contributes to individual variation, evolution, and disease. It has been argued that stochastic somatic genome instability makes an early and important contribution to the development of human cancer, largely through loss of wild-type tumor suppressor genes. Many tumor suppressor genes themselves are guardians of genome structure and proper cell cycle control, and their loss may cause additional somatic instability. Thus, high levels of genomic instability may be viewed as possible cause and/or effect of steps in tumorigenesis. To distinguish these, a method is needed for continuous monitoring of genome stability in cell lineages that give rise to cancer. Genome stability in vertebrates is currently followed using karyotype analysis, fluorescence in situ hybridization, or measurement of endogenous marker loss using cell selection procedures. At this time, an in vivo system that can be used to determine genome stability in situ (i.e., without tissue disruption) is lacking. We propose the zebrafish Danio rerio as an ideal model system in which to develop this view of vertebrate biology, and we outline a novel method for following marker stability in fish. The method is based on a transcriptional repression design in which repressor loss leads to expression of the fluorescent protein EGFP. Using transgenic zebrafish, we will perform proof-of-concept tests for detection of repressor loss and characterization of repressor loss mechanisms. The zebrafish is ideally suited for development of this strategy due to the ease of organ visualization and its well-developed genetics and genomics tools. Furthermore, the rapid generation time and small size of the zebrafish supports cost-effective observation of many individuals, providing statistical power. In future work, this measurement of genome stability in situ will be important for understanding the relationship between gene function and genome instability in different tissues, and between genome instability and tumor development.